Fetal Alcohol Exposure and the Brain
Nearly 30 years ago, scientists first coined the term "fetal alcohol
syndrome" (FAS) to describe a pattern of birth defects found in
children of mothers who consumed alcohol during pregnancy (1, 2).
Today, FAS remains the leading known preventable cause of mental
retardation (3). Behavioral and neurological problems associated
with prenatal alcohol exposure may lead to poor academic
performance, as well as legal and employment difficulties in
adolescence and adulthood (4). Despite attempts to increase public
awareness of the risks involved, increasing numbers of women are
drinking during pregnancy (5). This bulletin updates
Alcohol Alert No.
13 with new data on the prevalence and nature of the
neurobehavioral problems associated with alcohol use during
pregnancy, explores potential mechanisms underlying alcohol-induced damage to the developing brain and
discusses prevention research.
Definitions and Incidence
FAS is defined by four criteria: maternal drinking during pregnancy, a characteristic pattern of facial
abnormalities, growth retardation and brain damage, which often is manifested by intellectual difficulties or
behavioral problems (3). When signs of brain damage appear following fetal alcohol exposure in the absence of
other indications of FAS, the condition is termed "alcohol-related neurodevelopmental disorder" (ARND) (3).
Investigators have used both passive and active methods to determine the overall incidence of FAS and ARND.
The passive approach uses data collected from existing medical records, which are often based on information
recorded at birth. However, the criteria required for these diagnoses may not be apparent at birth and often
develop gradually from infancy through the first few years of grade school (6). In the active approach,
investigators use a defined set of diagnostic criteria to screen all members of a selected population for FAS and
other alcohol-related problems. Although both strategies have limitations, active ascertainment provides more
accurate prevalence data for the study population, especially if children are examined at elementary school age
(3). For example, a comprehensive survey of 992 first-grade students in 12 of the 13 elementary schools in a
South African community revealed an FAS incidence of more than 40 FAS cases per 1,000 births among children
ages 5 to 9 (7). In the United States, a preliminary active ascertainment of FAS in a single county in Washington
State yielded a minimum estimate of 3.1 per 1,000 first-grade students (8). By comparison, passive estimates of
FAS rates range from 0.33 to 3 infants per 1,000 births (3, 9).
Specific Cognitive and Behavioral Impairments
The broad range of cognitive and behavioral disabilities associated with
prenatal alcohol exposure was attributed by many researchers to a
generalized impairment of mental functioning. However, recent studies on FAS
and ARND reveal that specific neurobehavioral functions are consistently
impaired, whereas others are spared (10-13). Thus, the outlook for persons
diagnosed with FAS or ARND should not be considered hopeless (14, 15).
Some specific neurobehavioral impairments associated with prenatal alcohol
exposure are discussed below.
Verbal Learning. Children prenatally exposed to alcohol exhibit a variety of
problems with language and memory (3, 10). For example, Mattson and
colleagues (11) found that children with FAS ages 5 to 16 learned fewer words
compared with a group of children of comparable mental age who did not have
FAS. However, both groups demonstrated equal ability to recall information
learned previously. These findings indicate that FAS-related learning problems
occur during the initial stages of memory formation (i.e., encoding). Once
encoded, verbal information can be retained and recalled, subject to normal
rates of forgetting (11, 13). Clinically, this pattern helps distinguish FAS from Down's Syndrome, in which learning
and recall are equally impaired (16).
Visual-Spatial Learning. Children of mothers who drank heavily during pregnancy perform poorly on tasks that
involve learning spatial relationships among objects. In one experiment, groups of children with and without FAS
were equal in their ability to recall common, small household and schoolroom objects (e.g., a paper clip or
spoon) that had been placed within sight on a table and then removed (17). However, children with FAS had
greater difficulty subsequently restoring the objects to their original positions on the table (17).
Attention. Attention problems have been considered a hallmark of prenatal alcohol exposure (13).
Consequently, FAS is often incorrectly diagnosed as attention deficit hyperactivity disorder (ADHD) and treated
inappropriately (18). Coles and colleagues (18) found that children with ADHD exhibited difficulty focusing and
sustaining attention over time. In contrast, children who were exposed to alcohol prenatally were able to focus
and maintain attention, but displayed difficulty in shifting attention from one task to another (i.e., set shifting) (18).
Reaction Time. Individual differences in intelligence are based in part on how quickly the brain processes
information. Prenatal alcohol exposure has been associated with slower, less efficient information processing in
school-age children (19). Jacobson and colleagues (20) found similar problems in children as young as 6 1/2
months. These researchers recorded the eye movements of infants reacting to the appearance, movement and
disappearance of a repeating sequence of geometric designs and colors on a video screen. Maternal drinking
during pregnancy was related to longer reaction times among the children, suggesting slower, less efficient
information processing (20).
Executive Functions. Important deficits in FAS involve executive functions (i.e., activities that require abstract
thinking, such as planning and organizing). For example, problems with set shifting are common, as noted earlier.
Children prenatally exposed to alcohol respond poorly when asked to switch from naming animals to naming
types of furniture, and then back to naming animals (21). They also have difficulty abandoning demonstrably
ineffective strategies when approaching problem-solving tasks (21, 22), a type of behavioral inflexibility referred
to as perseveration. Perseveration and impaired set shifting are consistent with distractibility and impulsivity,
factors that at least theoretically might contribute to attention and learning problems (11, 22, 23).
Effects on Brain Structure
The behavioral and cognitive impairments associated with FAS reflect underlying structural or functional changes
in the brain (24). Techniques for viewing the living brain, such as magnetic resonance imaging (MRI), reveal
reduced overall brain size in persons with FAS and disproportionate reductions in the size of specific brain
structures (24).
One such area is the deep-brain structure called the basal ganglia (25, 26). Damage to the basal ganglia impairs
spatial memory and set shifting in animals (26, 27) and various cognitive processes in humans (28). Another
common finding is reduced size of the cerebellum (25, 29), a structure involved in balance, gait, coordination and
cognition (30). Finally, prenatal alcohol exposure is the major cause of impaired development (30) or complete
absence (30, 31) of the corpus callosum, a band of nerve fibers that forms the major communication link between
the right and left halves of the brain. Approximately 7 percent of children with FAS may lack a corpus callosum,
an incidence rate 20 times higher than that in the general population (30).
Potential Causal Mechanisms
The mechanisms that underlie alcohol-induced fetal brain damage
have been studied in experimental animals and in nerve cells (i.e.,
neurons) grown in culture (32). Within the fetus, embryonic cells
destined to become brain neurons grow in number, move to their
ultimate locations and mature into a wide variety of functionally
distinct neuronal cell types, eventually forming connections with
other brain cells in a predetermined pattern. Alcohol metabolism is
associated with increased susceptibility to cell damage caused by
potentially harmful substances called free radicals. Free radical
damage can kill sensitive populations of brain cells at critical times
of development in the first trimester of pregnancy (33, 34). Other
animal experiments suggest that the third trimester may also represent a particularly sensitive period for brain
cell damage associated with FAS (35).
Alcohol or its metabolic breakdown products can also interfere with brain development by altering the production
or function of natural regulatory substances that help promote the orderly growth and differentiation of neurons
(32). Research using animals or cell cultures show that many of alcohol's adverse effects on brain cells can be
prevented by treatments aimed at restoring the balance of regulatory substances upset by alcohol (36, 37).
Promising results have also been obtained in similar experiments by administering substances (i.e., antioxidants)
that help protect cells against free radical-induced cell damage (38). This is only one of several potential
mechanisms that may contribute to alcohol-related fetal injury. Further research is needed to determine if such
an approach might prove both effective and safe in humans during pregnancy.
Effect of Maternal Drinking Levels
The minimum quantity of alcohol required to produce adverse fetal consequences is unknown (22). Clinically
significant deficits are not common in children whose mothers drank less than approximately five drinks per
occasion once per week (39). However, vulnerability to a given alcohol level during pregnancy varies markedly
from person to person, possibly reflecting genetic factors, nutritional status, environmental factors, co-occurring
diseases and maternal age (40). Prospects for Prevention FAS and ARND could be completely eliminated if
pregnant women did not consume alcohol. Therefore, recent FAS prevention research has focused on finding
and treating women who drink during pregnancy. For example, TWEAK (41) - a brief questionnaire for assessing
alcohol problems in women - shows promise as a screening instrument for identifying risk drinking by pregnant
women (42).
Pregnant women who are consuming alcohol but are not "problem" drinkers may decrease their drinking level
following such an assessment without subsequent treatment (43). An overall decline in alcohol consumption has
also been noted among pregnant women following a brief intervention, which can be conducted by a primary
care provider (43). Such sessions may include a discussion of the risks of maternal drinking and suggested
alternatives to alcohol use. Pregnant women with higher drinking levels may benefit from a 1-hour motivational
interview focusing on the health of the unborn child (44). Women who are alcohol dependent require intensive
alcoholism treatment (44).
Fetal Exposure and the Brain - A Commentary by NIAAA Director Enoch Gordis, M.D.
Since our last
Alcohol Alert on FAS, published in 1991, the pace of research on the effects of alcohol on the
fetus has accelerated appreciably. Progress has been made most notably in research aimed at understanding
the basic mechanisms involved in the neurobiological damage that occurs in alcohol-exposed fetuses and in
developing potential new therapies to prevent that damage. We also have increased our understanding of the
long-term cognitive and physical challenges of children who were exposed to alcohol in the womb. As a result,
clinicians and behavioral scientists are finding ways to identify these children early and ways to help.
Despite the many gains in knowledge, we still do not know if there is a "safe" dose of alcohol that can be
consumed by pregnant women without risking damage to their unborn children. Until such a safe dose, if it exists,
can be determined, the only responsible advice to women who wish to become pregnant and to those who are
pregnant is to avoid alcohol use entirely. Unfortunately, many women continue to drink during pregnancy.
Furthermore, many of the women who continue to drink during pregnancy are at highest risk for having children
with fetal alcohol syndrome and related problems. Thus, finding potent new ways to reach populations at risk
and to influence changes in their behavior remains a challenge for alcohol research.
NOTE:
NIAAA has developed two new guides to provide clinicians with office-based screening and intervention protocols
for alcohol-related birth defects: Identification of At-Risk Drinking and Intervention with Women of Childbearing
Age (NIH Pub. No. 99-4368) and Identification and Care of Fetal Alcohol-Exposed Children (NIH Pub. No.
99-4369). Both can be ordered through NIAAA's Web site at http://www.niaaa.nih.gov (from the homepage, click
on "Publications"); by fax at (202) 842-0418; or by writing to NIAAA Publications Distribution Center, P.O. Box
10686, Rockville, MD 20849-0686. Please specify the appropriate publication number(s) when ordering.
References
(1) Lemoine, P.; Harousseau, H.; Borteyru, J.P.; and Menuet, J.C. Les enfants de parents alcooliques:
Anomalies observées à propos de 127 cas. Ouest Med 21:476-482, 1968.
(2) Jones, K.L., and Smith, D.W.
Recognition of the fetal alcohol syndrome in early infancy. Lancet 2:999-1001, 1973.
(3) Stratton, K.; Howe, C.;
and Battaglia, F., eds. Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment.
Washington, D.C.: National Academy Press, 1996.
(4) Thomas, S.E.; Kelly, S.J.; Mattson, S.N.; and Riley, E.P.
Comparison of social abilities of children with fetal alcohol syndrome to those of children with similar IQ scores
and normal controls. Alcohol Clin Exp Res 22(2):528-533, 1998.
(5) Ebrahim, S.H.; Diekman, S.T.; Floyd, R.L.;
and Decoufle, P. Comparison of binge drinking among pregnant and nonpregnant women, United States,
1991-1995. Am J Obstet Gynecol 180(1, Part 1):1-7, 1999.
(6) Aase, J.M. Clinical recognition of FAS:
Difficulties of detection and diagnosis. Alcohol Health Res World 18(1):5-9, 1994.
(7) May, P.A.; Brooke, L.;
Gossage, J.P.; et al. Epidemiology of fetal alcohol syndrome in a South African community in the Western Cape
Province. Am J Pub Health 90(12):1905-1912, 2000.
(8) Clarren, S.K.; Randels, S.P.; Sanderson, M.; and
Fineman, R.M. Screening for fetal alcohol syndrome in primary schools: A feasibility study. Teratology
63(1):3-10, 2001.
(9) Abel, E.L., and Sokol, R.J. A revised conservative estimate of the incidence of FAS and
its economic impact. Alcoholism: Clin Exp Res 15(3):514-524, 1991.
(10) Janzen, L.A.; Nanson, J.L.; and Block,
G.W. Neuropsychological evaluation of preschoolers with fetal alcohol syndrome. Neurotoxicol Teratology
17(3):273-279, 1995.
(11) Mattson, S.N.; Riley, E.P.; Delis, D.C.; Stern, C.; and Jones, K.L. Verbal learning and
memory in children with fetal alcohol syndrome. Alcohol Clin Exp Res 20(5):810-816, 1996a.
(12) Olson, H.C.;
Feldman, J.J.; Streissguth, A.P.; Sampson, P.D.; and Bookstein, F.L. Neuropsychological deficits in adolescents
with fetal alcohol syndrome: Clinical findings. Alcohol Clin Exp Res 22(9):1998-2012, 1998.
(13) Mattson, S.N.,
and Riley, E.P. A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal
exposure to alcohol. Alcohol Clin Exp Res 22(2):279-294, 1998.
(14) Mattson, S.N.; Riley, E.P.; Gramling, L.;
et al. Neuropsychological comparisons of alcohol-exposed children with or without physical features of fetal
alcohol syndrome. Neuropsychology 12(1):146-153, 1998.
(15) Ernhart, C.B.; Greene, T.; Sokol, R.J.; et al.
Neonatal diagnosis of fetal alcohol syndrome: Not necessarily a hopeless prognosis. Alcohol Clin Exp Res
19(6):1550-1557, 1995.
(16) Mattson, S.N.; Goodman, A.M.; Caine, C.; Delis, D.C.; and Riley, E.P. Executive
functioning in children with heavy prenatal alcohol exposure. Alcohol Clin Exp Res 23(11):1808-1815, 1999.
(17) Uecker, A., and Nadel, L. Spatial locations gone awry: Object and spatial memory deficits in children with
fetal alcohol syndrome. Neuropsychologia 34(3):209-223, 1996.
(18) Coles, C.D.; Platzman, K.A.;
Raskind-Hood, C.L.; et al. A comparison of children affected by prenatal alcohol exposure and attention deficit,
hyperactivity disorder. Alcohol Clin Exp Res 21(1):150-161, 1997.
(19) Streissguth, A.P.; Barr, H.M.; Sampson,
P.D.; et al. Attention, distraction, and reaction time at age 7 years and prenatal alcohol exposure. Neurobehav
Toxicol Teratology 8(16):717-725, 1986.
(20) Jacobson, S.W.; Jacobson, J.L.; and Sokol, R.J. Effects of fetal
alcohol exposure on infant reaction time. Alcohol Clin Exp Res 18(5):1125-1132, 1994.
(21) Kodituwakku, P.W.;
Handmaker, N.S.; Cutler, S.K.; Weathersby, E.K.; and Handmaker, S.D. Specific impairments in self-regulation in
children exposed to alcohol prenatally. Alcohol Clin Exp Res 19(6):1558-1564, 1995.
(22) Roebuck, T.M.;
Mattson, S.N.; and Riley, E.P. Behavioral and psychosocial profiles of alcohol-exposed children. Alcohol Clin Exp
Res 23(6):1070-1076, 1999.
(23) Hunt, E.; Streissguth, A.P.; Kerr, B.; and Olson, H.C. Mothers' alcohol
consumption during pregnancy: Effects on spatial-visual reasoning in 14-year-old children. Psychol Science
6(6):339-342, 1995.
(24) Roebuck, T.M.; Mattson, S.N.; and Riley, E.P. A review of the neuroanatomical findings
in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol Clin Exp Res 22(2):339-344,
1998.
(25) Mattson, S.N.; Riley, E.P.; Jernigan, T.L.; et al. A decrease in the size of the basal ganglia following
prenatal alcohol exposure: A preliminary report. Neurotoxicol Teratology 16(3):283-289, 1994.
(26) Mattson,
S.N.; Riley, E.P.; Sowell, E.R.; et al. A decrease in the size of the basal ganglia in children with fetal alcohol
syndrome. Alcohol Clin Exp Res 20(6):1088-1093, 1996b.
(27) Mattson, S.N., and Riley, E.P. Implicit and
explicit memory functioning in children with heavy prenatal alcohol exposure. J Int Neuropsychol Soc
5(5):462-471, 1999.
(28) Bannister, R. Brain and Bannister's Clinical Neurology. 7th ed. New York: Oxford
University Press, 1992.
(29) Sowell, E.R.; Jernigan, T.L.; Mattson, S.N.; et al. Abnormal development of the
cerebellar vermis in children prenatally exposed to alcohol: Size reduction in lobules I-V. Alcohol Clin Exp Res
20(1):31-34, 1996.
(30) Riley, E.P.; Mattson, S.N.; Sowell, E.R.; et al. Abnormalities of the corpus callosum in
children prenatally exposed to alcohol. Alcohol Clin Exp Res 19(5):1198-1202, 1995.
(31) Swayze, II, V.W.;
Johnson, V.P.; Hanson, J.W.; et al. Magnetic resonance imaging of brain anomalies in fetal alcohol syndrome.
Pediatrics 99(2):232-240, 1997.
(32) Michaelis, E.K., and Michaelis, M.L. Cellular and molecular bases of
alcohol's teratogenic effects. Alcohol Health Res World 18(1):17-21, 1994.
(33) Cartwright, M.M., and Smith,
S.M. Increased cell death and reduced neural crest cell numbers in ethanol-exposed embryos: Partial basis for
the fetal alcohol syndrome. Alcohol Clin Exp Res 19(2):378-386, 1995.
(34) Chen, S., and Sulik, K.K. Free
radicals and ethanol-induced cytotoxicity in neural crest cells. Alcohol Clin Exp Res 20(6):1071-1076, 1996.
(35) Maier, S.E.; Chen, W.-J.A.; and West, J.R. The effects of timing and duration of alcohol exposure on
development of the fetal brain. In: Abel, E.L., ed. Fetal Alcohol Syndrome: From Mechanism to Prevention. Boca
Raton, Florida: CRC Press, 1996. pp. 27-50.
(36) Luo, J.; West, J.R.; and Pantazis, N.J. Nerve growth factor
and basic fibroblast growth factor protect rat cerebellar granule cells in culture against ethanol-induced cell
death. Alcohol Clin Exp Res 21(6):1108-1120, 1997.
(37) Tajuddin, N.F., and Druse, M.J. In utero ethanol
exposure decreased the density of serotonin neurons: Maternal ipsapirone treatment exerted a protective effect.
Del Brain Res 117(1):91-97, 1999.
(38) Heaton, M.B.; Mitchell, J.J.; and Paiva, M. Amelioration of
ethanol-induced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy. Alcohol Clin
Exp Res 24(4):512-518, 2000.
(39) Jacobson, J.L., and Jacobson, S.W. Drinking moderately and pregnancy:
Effects on child development. Alcohol Res Health 23(1):25-30, 1999.
(40) Abel, E.L., and Hannigan, J.H.
Maternal risk factors in fetal alcohol syndrome: Provocative and permissive influences. Neurotoxicol Teratology
17(4):445-462, 1995.
(41) Russell, M. New assessment tools for risk drinking during pregnancy: T-ACE,
TWEAK, and others. Alcohol Health Res World 18(1):55-61, 1994.
(42) Chang, G.; Wilkins-Haug, L.; Berman,
S.; and Goetz, M.A. The TWEAK: Application in a prenatal setting. J Stud Alcohol 60(3):306-309, 1999a.
(43) Chang, G.; Wilkins-Haug, L.; Berman, S.; and Goetz, M.A. Brief intervention for alcohol use in pregnancy:
A randomized trial. Addict 94(10):1499-1508, 1999b.
(44) Handmaker, N.S.; Miller, W.R.; and Manicke, M.
Findings of a pilot study of motivational interviewing with pregnant drinkers. J Stud Alcohol 60(2):285-287, 1999.
